Composition for sustained drug delivery comprising geopolymeric binder

ABSTRACT

The present invention relates to a sustained release medical composition comprising an active pharmaceutical ingredient and a geopolymeric binder. Preferably the active pharmaceutical ingredient is combined with the geopolymeric binder during the formation of that binder.

RELATED APPLICATIONS

This application is a continuation of co-pending application Ser. No.13/319,201, filed 27 Apr. 2012, which is a 371 of Internationalapplication Serial No. PCT/GB2010/000910 filed 7 May 2010.

FIELD OF THE INVENTION

This invention relates to new, non-abusable pharmaceutical compositions(drug delivery systems; DDSs) that provide for the controlled release ofactive pharmaceutical ingredients (APIs), such as opioid analgesics, ine.g. the gastrointestinal tract. The invention also relates to methodsof manufacturing such DDSs.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Opioids are widely used in medicine as analgesics, for example in thetreatment of patients with severe pain, chronic pain, or to manage painafter surgery. Indeed, it is presently accepted that, in the palliationof more severe pain, no more effective therapeutic agents exist.

The term “opioid” is typically used to describe an API that activatesopioid receptors, which are found in the brain, the spinal cord and thegut. Three classes of opioids exist:

(a) naturally-occurring opium alkaloids. These include morphine andcodeine;

(b) compounds that are similar in their chemical structure to thenaturally-occurring opium alkaloids. These so-called semi-synthetics areproduced by chemical modification of the latter and include the likes ofdiamorphine (heroin), oxycodone and hydrocodone; and

(c) truly synthetic compounds such as fentanyl and methadone. Suchcompounds may be completely different in terms of their chemicalstructures to the naturally-occurring compounds.

Of the three major classes of opioid receptors (μ, κ and δ), opioids'analgesic and sedative properties mainly derives from agonism at the μreceptor.

Opioid analgesics are used to treat the severe, chronic pain of terminalcancer, often in combination with non-steroid anti-inflammatory drugs(NSAIDs), as well as acute pain (e.g. during recovery from surgery).Further, their use is increasing in the management of chronic,non-malignant pain.

Optimal management of chronic pain requires around-the-clock coverage.In this respect, opioid-requiring cancer patients are usually givenslow-release opiates (slow-release morphine, oxycodone or ketobemidone,or transdermal fentanyl). DDSs that are capable of providing a sustainedrelease of such APIs allow the patient to obtain this baseline analgesiawith a minimal number of doses per day. This in turn improves patientcompliance and minimizes interference with the individual's lifestyleand therefore quality of life.

Transdermal fentanyl DDSs comprise patches (e.g. DURAGESIC®) that areapplied to the skin to deliver that potent opioid analgesic, which isslowly absorbed through the skin into systemic circulation. Pain may berelieved for up to three days from a single patch application.

However, such patches do not provide for a constant plasma level of APIover the entire application period. This defect is an inevitableconsequence of the fact that transdermal administration of fentanylgives rise to the formation of a fentanyl depot in skin tissue. Serumfentanyl concentrations increase gradually following initial applicationof a patch, generally levelling off between 12 and 24 hours beforereaching a saturation point, whereafter absorption of API remainsrelatively constant, with some fluctuation, for the remainder of the72-hour application period.

Furthermore, firstly, in the design of sustained release DDSs withextremely potent APIs, such as opioids, the risk for “dose dumping” hasto be eliminated in view of the risk of severe and, on occasions, lethalside effects. Secondly, a perennial problem with potent opioidanalgesics such as fentanyl is one of abuse by drug addicts. Addictsnormally abuse DDSs by one or more of the following processes:

(i) extracting a large quantity of API from that DDS using acid and/oralcohol into solution, which is then injected intravenously. With mostcommercially-available DDSs, this can be done relatively easily, whichrenders them unsafe or “abusable”;

(ii) heating (and then smoking);

(iii) crushing of tablet (and then snorting); and/or

(iv) in the case of a patch, making a tea (and then drinking).

Thus, there is a clear unmet clinical need for an effective DDS that iscapable of treating e.g. severe pain via a sustained release of APIs(such as opioid analgesics), whilst at the same time minimising thepossibility of dose dumping and/or abuse by addicts.

Ceramics are becoming increasingly useful to the medical world, in viewof the fact they are durable and stable enough to withstand thecorrosive effect of body fluids.

For example, surgeons use bioceramic materials for repair andreplacement of human hips, knees, and other body parts. Ceramics alsoare being used to replace diseased heart valves. When used in the humanbody as implants or even as coatings to metal replacements, ceramicmaterials can stimulate bone growth, promote tissue formation andprovide protection from the immune system. Dental applications includethe use of ceramics for tooth replacement implants and braces.

Ceramics are also known to be of potential use as fillers or carriers incontrolled-release DDSs. See, for example, EP 947 489 A, U.S. Pat. No.5,318,779, WO 2008/118096, Lasserre and Bajpai, Critical Reviews inTherapeutic Drug Carrier Systems, 15, 1 (1998), Byrne and Deasy, Journalof Microencapsulation, 22, 423 (2005) and Levis and Deasy, Int. J.Pharm., 253, 145 (2003).

In particular, Rimoli et al, J. Biomed. Mater. Res., 87A, 156 (2008), USpatent application 2006/0165787 and international patent applications WO2006/096544, WO 2006/017336 and WO 2008/142572 all disclose variousceramic substances for controlled release of APIs, with the latter twodocuments being directed in whole or in part to opioid analgesics, withthe abuse-resistance being imparted by the ceramic structures'mechanical strength.

Methods employed in these documents typically involve the incorporationof APIs into pre-formed porous ceramic materials comprising e.g. poroushalloysite, kaolin, titanium oxide, zirconium oxide, scandium oxide,cerium oxide and yttrium oxide. In this respect, loading of APItypically comprises soaking, extrusion-spheronization and/orcryopelletization in the prior art.

Ceramic carriers are also optionally mixed with traditional excipientsto form tablets or the like. It is known to be difficult to infuse druginto a pre-formed porous ceramic structure. Indeed, in the case ofopioids, it is considered that such API-incorporation methodology willnot enable the loading of sufficient API to provide appropriate dosesfor effective therapeutic pain management, over a prolonged time, giventhat infusion of API into preformed pores is a difficult thing to do.

In WO 2008/142572, drugs are incorporated during the formation of aceramic carrier using chemically bonded ceramics, such as calciumaluminate or calcium silicate. Although this leads to a higher amount ofdrug incorporation than is typically the case for preformed ceramicmaterials, the mechanical strength and the chemical stability of theceramic structures described in WO 2008/142572 is, relatively speaking,limited, especially in acidic conditions.

There is thus a presently unmet clinical need for a DDS that impartssustained release of potent APIs over extended periods of time combinedwith a low risk of dose dumping and/or drug diversion (abuse).

DISCLOSURE OF THE INVENTION

According to the invention, there is provided a sustained release DDS inwhich an API, or a pharmaceutically acceptable salt thereof, is combinedwith a geopolymeric binder, preferably during the formation of thelatter, which DDSs are referred to hereinafter together as “the DDSs ofthe invention”.

The term “sustained-release” is employed herein synonymously with theterm “controlled-release”, and will be understood by the skilled personto include DDSs that provide, and/or are adapted to provide, for a“sustained”, a “prolonged” and/or an “extended” release of API (in whichAPI is released at a sufficiently retarded rate to produce a therapeuticresponse over a required period of time).

The term “geopolymer” will be understood by those skilled in the art toinclude or mean any material selected from the class of synthetic ornatural aluminosilicate materials which may be formed by reaction of analuminosilicate precursor material (preferably in the form of a powder)with an aqueous alkaline liquid (e.g. solution), preferably in thepresence of a source of silica.

The term “source of silica” will be understood to include any form of asilicon oxide, such as SiO

2, including a silicate. The skilled person with appreciate that silicamay be manufactured in several forms, including glass, crystal, gel,aerogel, fumed silica (or pyrogenic silica) and colloidal silica (e.g.Aerosil).

Suitable aluminosilicate precursor materials are typically (but notnecessarily) crystalline in their nature include kaolin, dickite,halloysite, nacrite, zeolites, illite, preferably dehydroxylatedzeolite, halloysite or kaolin and, more preferably, metakaolin (i.e.dehydroxylated kaolin). Dehydroxylation (of e.g. kaolin) is preferablyperformed by calcining (i.e. heating) of hydroxylated aluminosilicate attemperatures above 400° C. For example, metakaolin may be prepared asdescribed by Stevenson and Sagoe-Crentsil in J. Mater. Sci., 40, 2023(2005) and Zoulgami et al in Eur. Phys J. AP, 19, 173 (2002), and/or asdescribed hereinafter. Dehydroxylated aluminosilicate may also bemanufactured by condensation of a source of silica and a vapourcomprising a source of alumina (e.g. Al2O3).

Precursor materials may also be manufactured using sol-gel methods,typically leading to nanometer sized amorphous powder (or partlycrystalline) precursors of aluminosilicate, as described in Zheng et alin J. Materials Science, 44, 3991-3996 (2009).

If provided in the form of a powder, the grain size of thealuminosilicate precursor particles are below about 500 μm, preferablybelow about 100 μm, more preferred below about 30 μm.

In the formation of geopolymer materials, such precursor materials maybe dissolved in an aqueous alkaline solution, for example with a pHvalue of at least about 12, such as at least about 13. Suitable sourcesof hydroxide ions include strong inorganic bases, such as alkali oralkaline earth metal (e.g. Ba, Mg or, more preferably, Ca or, especiallyNa or K, or combinations thereof) hydroxides (e.g. sodium hydroxide).

The molar ratio of metal cation to water can vary between about 1:100and about 10:1, preferably between about 1:20 and about 1:2.

A source of silica (e.g. a silicate, such as SiO2) is preferably addedto the reaction mixture by some means. For example, the aqueous alkalineliquid may comprise SiO2, forming what is often referred to aswaterglass, i.e. a sodium silicate solution. In such instances, theamount SiO2 to water in the liquid is preferably up to about 2:1, morepreferably up to about 1:1, and most preferably up to about 1:2. Theaqueous liquid may also optionally contain sodium aluminate.

Silicate (and/or alumina) may alternatively be added to the optionallypowdered aluminosilicate precursor material, preferably as fume silica(microsilica; AEROSIL® silica). The amount that may added is preferablyup to about 30 wt %, more preferably up to about 5 wt % of thealuminosilicate precursor.

The presence of free hydroxide ions in this intermediate alkalinemixture, causes aluminium and silicon atoms from the source material(s)to be dissolved. The geopolymer materials may then be formed by allowingthe resultant mixture to set (cure or harden), during which process thealuminium and silicon atoms from the source materials reorientate toform a hard (and at least largely) amorphous geopolymeric material.Curing may be performed at room temperature, at elevated temperature orat reduced temperature, for example at around or just above ambienttemperature (e.g. between about 20° C. and about 90° C. (e.g. 50° C.),such as around 40° C.). The hardening may also be performed in anyatmosphere, humidity or pressure (e.g. under vacuum or otherwise). Theresultant inorganic polymer network is in general a highly-coordinated3-dimensional aluminosilicate gel, with the negative charges ontetrahedral Al3+ sites charge-balanced by alkali metal cations.

In this respect, in a preferred embodiment, the DDS may be formed bymixing a powder comprising the aluminosilicate precursor and an aqueousliquid (e.g. solution) comprising water, a source of hydroxide ions asdescribed hereinbefore and the source of silica (e.g. silicate), to forma paste. The ratio of the liquid to the powder is preferably betweenabout 0.2 and about 20 (w/w), more preferably between about 0.3 andabout 10 (w/w).

In the process for formation of DDSs of the invention, API may be addedto preformed geopolymer, but is preferably included in the geopolymericbinder during the formation of the latter. Thus, the aqueous alkalineliquid may contain API, preferably up to about 30 wt %, more preferablyup to about 10 wt %, as calculated on the sum of all the ingredientsthat are included in that liquid. Alternatively, API may be added to thealuminosilicate precursor component prior to mixing with the aqueousalkaline liquid. The amount of API added to the precursor component maybe up to about 70 wt %, and preferably between about 3 and about 10 wt%, of the total powder weight.

Curing may be performed by allowing the paste to harden into any givenshape, e.g. blocks, pellets, granules or a powder.

In this respect, the paste may be transferred into moulds and left toset as pellets/granules or alternatively (e.g. preferably)pellets/granules may be manufactured using an appropriateextrusion-spheronization technique. Here, the formed paste (powder andliquid mixture) may be extruded through an orifice. The size of theorifice may be from about 10 μm up to about 30 mm, preferably from about100 μm to about 1 mm. The formed extrudate may then be placed in aspheronizer, which is typically a vertical hollow cylinder with ahorizontal rotating disk located inside. When the disk is spun, theextrudate is broken into uniform lengths and gradually formed intospherical pellets, which may then be left to harden as describedhereinbefore.

Suitable pellet/granule sizes are in the range of about 0.05 mm to about3.0 mm (e.g. about 2.0 mm, such as about 1.7 mm), and preferably about0.1 mm (e.g. about 0.2 mm) to about 1.6 mm (e.g. about 1.5 mm), such asabout 1 mm.

The DDSs of the invention may further comprise one or morecommonly-employed pharmaceutical excipients. Suitable excipients includeinactive substances that are typically used as a carrier for the APIs inmedications. Suitable excipients also include those that are employed inthe pharmaceutical arts to bulk up DDSs that employ very potent APIs, toallow for convenient and accurate dosing. Alternatively, excipients mayalso be employed in manufacturing processes of the DDSs of the inventionto aid in the handling of the API concerned.

In this respect, pharmaceutically-acceptable excipients include fillerparticles, by which we include particles that do not take part in thechemical reaction during which the geopolymeric binder-based DDS of theinvention is formed. Such filler particles may be added as ballastand/or may provide the DDS with functionality. Non-limiting examplesinclude: zirconium dioxide and barium sulfate to increase radio-opacity,which may be added to smaller particles (e.g. milled) DDS according tothe present invention (including the API). DDSs according to theinvention may thus comprise particles comprising:

(i) inert fillers, such as those mentioned hereinbefore;

(ii) DDS including API; and/or

(iii) other API-loaded porous ceramic particles (e.g. for sustainedrelease) bound together by geopolymer.

DDSs of the invention may alternatively be milled to a fine powder,preferably with a powder grain size of below about 100 μm, and morepreferably below about 20 μm. Milling is optionally performed usingball-milling, planetary ball-milling, jet milling or a combinationthereof. The amount of added filler particles may be up to about 80 wt%, preferably up to about 40 wt % of the aluminosilicate precursorweight.

The alkaline liquid or aluminosilicate precursor may also optionallycontain bulking agents, porogens, dispersion agents or gelating agentsto control the rheology or the amount of liquid in the geopolymer. Thetotal amount of such excipients is limited to about 20 wt % of the totalweight of the precursor and liquid combined. Non-limiting examples ofsuch excipients include polycarboxylic acids, cellulose,polyvinylalchol, polyvinylpyrrolidone, starch, nitrilotriacetic acid(NTA), polyacrylic acids, PEG, sorbitol, mannitol and combinationsthereof.

Additional pharmaceutically-acceptable excipients include carbohydratesand inorganic salts such as sodium chloride, calcium phosphates, calciumcarbonate. Such additional materials are preferably added to thealuminosilicate precursor component. Calcium silicate and calciumaluminate may also be added to the aluminosilicate precursor component.

DDSs of the invention may also comprise film-forming agents. The term“film-forming agent” refers to a substance that is capable of forming afilm over (or within), or coating over, another substance (which may bein particulate form).

It is preferred that the film-forming agent is a material that iscapable of providing a sustained-release, delayed-release or,preferably, enteric-release coating (i.e. an enteric coating material).Substances that are capable of providing an enteric coating are thusthose that may be employed in peroral DDSs as a barrier to prevent orminimise release of API prior to such DDSs reaching the small intestine.

In this respect, it is preferred that the film-forming agent is apolymer. Examples of polymers that may be employed as film-formingagents include, without limitation: alkylcellulose polymers (e.g.ethylcellulose polymers), and acrylic polymers (e.g. acrylic acid andmethacrylic acid copolymers, methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, methyl methacrylate, copolymers, methacrylic acidcopolymers, methyl methacrylate copolymers, methyl methacrylatecopolymers, methacrylate copolymers, methacrylic acid copolymer,aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methylmethacrylate copolymers, poly(acrylic acid), poly(methacrylic acid,methacrylic acid alkylamide copolymer, poly(methyl methacryate),poly(methacrylic acid) (anhydride), methyl methacrylate,polymethacrylate, methyl methacrylate copolymer, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacryamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers). The polymer may also be a mixture ofpolymers. Typically, the molecular weight (weight average and/or numberaverage) of the polymer is 1,000 to 10,000,000, 10,000 to 1,000,000,preferably 50,000 to 500,000 g/mol, as measured by gel permeationchromatography.

Preferred polymers include the alkyl cellulose polymers and acrylicpolymers described herein.

Preferably, the film-forming agent comprises a polymer that exhibitsanionic character and/or is weakly acidic (for example that have a pH ofless than 7, and preferably less than 5).

The most preferred polymer includes that marketed under the trademarkKollicoat®. Kollicoat® comprises a copolymer derived from methacrylicacid and ethyl acrylate. Kollicoat® MAE 30 DP (BASF) is a copolymer ofmethacrylic acid/ethyl acrylate (1:1), and is available as an aqueousdispersion or powder. Other polymers that may be mentioned include thosemarketed under the trademark Eudragit®, which are neutral methacrylicpolymers with acid or alkaline groups.

DDSs of the invention may also comprise a pelletisation aid material. Apelletisation aid material may be defined as a material that is capableof controlling the distribution of granulating liquid through the wetpowder mass during pelletisation and to modify the rheologicalproperties in the mixture. Suitable pelletisation aid materials includehydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC) and,preferably, microcrystalline cellulose. If present, the pelletisationaid material is preferably employed in an amount of between 0.5 and 50%by weight based upon the total weight of the DDS. A preferred range isfrom 1 to 20%, such as from about 2.0 to about 12% (e.g. about 10%) byweight.

After hardening the DDS may contain unreacted aluminosilicate mineralbut consists essentially of a geopolymeric binder with the generalcomposition:M₂O*xSiO₂ *yAl₂O₃ *zH₂O

wherein

M is an alkali metal cation, preferably Na or K;

x is in the range of 0.1-300, preferably 1-50;

y is in the range of 0.1-100, preferably 0.5-10; and

z is in the range of 0.1-100, preferably 1-20.

APIs that may be employed in DDSs of the invention preferably includesubstances from various pharmacological classes, e.g. antibacterialagents, antihistamines and decongestants, anti-inflammatory agents,antiparasitics, antivirals, local anaesthetics, antifungals,amoebicidals or trichomonocidal agents, analgesics, antianxiety agents,anticlotting agents, antiarthritics, antiasthmatics, anticoagulants,anticonvulsants, antidepressants, antidiabetics, antiglaucoma agents,antimalarials, antimicrobials, antineoplastics, antiobesity agents,antipsychotics, antihypertensives, auto-immune disorder agents,anti-impotence agents, anti-Parkinsonism agents, anti-Alzheimer'sagents, antipyretics, anticholinergics, anti-ulcer agents,blood-glucose-lowering agents, bronchodilators, central nervous systemagents, cardiovascular agents, cognitive enhancers, contraceptives,cholesterol-reducing agents, agents that act against dyslipidermia,cytostatics, diuretics, germicidials, H2 blockers, hormonal agents,anti-hormonical agents, hypnotic agents, inotropics, muscle relaxants,muscle contractants, physical energizers, sedatives, sympathomimetics,vasodilators, vasocontrictors, tranquilizers, electrolyte supplements,vitamins, uricosurics, cardiac glycosides, membrane efflux inhibitors,membrane transport protein inhibitors, expectorants, purgatives,contrast materials, radiopharmaceuticals, imaging agents, peptides,enzymes, growth factors, vaccines and mineral trace elements. Other APIsubstances include proton pump inhibitors.

APIs that may be employed in DDSs of the invention preferably includeany that are open to abuse potential, such as those that are useful inthe treatment of acute or chronic pain, attention deficit hyperactivitydisorders (ADHD), anxiety and sleep disorders, as well as growthhormones (e.g. erythropoietin), anabolic steroids, etc. A full list ofpotentially abusable substances may be found by the skilled person, forexample on the weblinkhttp://www.deadiversion.usdoj.gov/schedules/alpha/alphabetical.htm.

Non-opioid APIs that may be specifically mentioned includepsychostimulants, such as modafinil, amphetamine, dextroamphetamine,methamphetamine and hydroxyamphethamine and, more preferably,methylfenidate; benzodiazepines, such as bromazepam, camazepam,chlordiazepoxide, clotiazepam, cloxazepam, delorazepam, estazolam,fludiazepam, flurazepam, halazepam, haloxazepam, ketazolam,lormetazepam, medazepam, nimetazepam, nordiazepam, oxazolam, pinazepam,prazepam, temazepam, tetrazepam and, more preferably, alprazolam,clonazepam, diazepam, flunitrazepam, lorazepam, midazolam, nitrazepam,oxazepam and triazolam; and other, non-benzodiazepine sedatives (e.g.short-acting hypnotics), such as zaleplon, zolpidem, zopiclone andeszopiclone.

DDSs of the invention may also find utility in the formulation of APIswhere crushing of a tablet may put the patient at risk, or may increasethe risk for adverse effects and/or an unpleasant taste. That is to say,those APIs where avoidance of one or more of the following is desirable:

i) a tablet being chewed before being swallowed;

ii) accidental destruction during passage through the gastrointestinaltract;

iii) release of API content as a consequence of concomitant intake of,for instance, alcoholic beverages, which may destroy the controlledrelease functionality of the DDS; and/or

iv) ex vivo tampering, i.e. crushing for subsequent abuse (vide infra),or for ease of subsequent swallowing, which may result in destruction ofthe functionality of the formulated API.

Such APIs will be well known to the skilled person, but may also befound for example on the weblinkhttp://www.ismp.org/Tools/DoNotCrush.pdf. Such APIs include those thatare used for the treatment of a variety of disorders where slow releaseDDSs are beneficial, including APIs that are employed in the treatmentof cardiovascular diseases (hypertension, heart failure), diabetes,asthma, CNS disorders and urogenital disorders, as well as antibiotics.

However, preferred APIs that may be employed in DDSs of the inventioninclude opioid analgesics. The term “opioid analgesic” will beunderstood by the skilled person to include any substance, whethernaturally-occurring or synthetic, with opioid or morphine-likeproperties and/or which binds to opioid receptors, particularly theμ-opioid receptor, having at least partial agonist activity, therebycapable of producing an analgesic effect. The problems of potential DDStampering and API extraction by drug addicts are particularly prominentwith opioids.

Opioid analgesics that may be mentioned include opium derivatives andthe opiates, including the naturally-occurring phenanthrenes in opium(such as morphine, codeine, the baine and Diels-Alder adducts thereof)and semisynthetic derivatives of the opium compounds (such asdiamorphine, hydromorphone, oxymorphone, hydrocodone, oxycodone,etorphine, nicomorphine, hydrocodeine, dihydrocodeine, metopon,normorphine and N-(2-phenylethyl)normorphine). Other opioid analgesicsthat may be mentioned include fully synthetic compounds with opioid ormorphine-like properties, including morphinan derivatives (such asracemorphan, levorphanol, dextromethorphan, levallorphan, cyclorphan,butorphanol and nalbufine); benzomorphan derivatives (such ascyclazocine, pentazocine and phenazocine); phenylpiperidines (such aspethidine (meperidine), fentanyl, alfentanil, sufentanil, remifentanil,ketobemidone, carfentanyl, anileridine, piminodine, ethoheptazine,alphaprodine, betaprodine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP), diphenoxylate and loperamide), phenylheptamines or “open chain”compounds (such as methadone, isomethadone, propoxyphene andlevomethadyl acetate hydrochloride (LAAM)); diphenylpropylaminederivatives (such as dextromoramide, piritramide, bezitramide anddextropropoxyphene); mixed agonists/antagonists (such as buprenorphine,nalorphine and oxilorphan) and other opioids (such as tilidine, tramadoland dezocine). Further opioid analgesics that may be mentioned includeallylprodine, benzylmorphine, clonitazene, desomorphine, diampromide,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethylmethylthiambutene,ethylmorphine, etonitazene, hydroxypethidine, levophenacylmorphan,lofentanil, meptazinol, metazocine, myrophine, narceine, norpipanone,papvretum, phenadoxone, phenomorphan, phenoperidine and propiram.

Non limiting examples of opioid analgesics include morphine, meperidine,fentanyl, hydromorphone, oxymorphone, oxycodone, hydrocodone, methadone,propoxyphene, pentazocine, levorphanol and codeine. Other APIs that maybe mentioned include, naloxone and acetaminophen and combinations ofthese with any of the opioid analgesics listed above or below.

More preferred opioid analgesics include buprenorphine, alfentanil,sufentanil, remifentanil and, particularly, fentanyl.

APIs listed above may be formulated in DDS according to the invention inany specific combination.

APIs may be employed in salt form or any other suitable form, such ase.g. a complex, solvate or prodrug thereof, or in any physical form suchas, e.g., in an amorphous state, as crystalline or part-crystallinematerial, as co-crystals, or in a polymorphous form or, if relevant, inany stereoisomeric form including any enantiomeric, diastereomeric orracemic form, or a combination of any of the above.

Pharmaceutically-acceptable salts of APIs that may be mentioned includeacid addition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of an API with one or more equivalents of an appropriate acidor base, optionally in a solvent, or in a medium in which the salt isinsoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of API in theform of a salt with another counter-ion, for example using a suitableion exchange resin.

Examples of pharmaceutically acceptable addition salts include thosederived from mineral acids, such as hydrochloric, hydrobromic,phosphoric, metaphosphoric, nitric and sulphuric acids; from organicacids, such as tartaric, acetic, citric, malic, lactic, fumaric,benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and frommetals such as sodium, magnesium, or preferably, potassium and calcium.

DDSs of the invention may possess one or more of the followingproperties:

(a) acid resistance, a necessary attribute for the DDS to possess whenpassing through the stomach following oral administration. In thisrespect, DDSs of the invention may show an insignificant degree (e.g.less than 1%) of chemical degradation or decomposition in aqueous acidmilieu (at pH values between about 0.1 and about of 4.0) at temperaturesin excess of room temperature (e.g. up to about 50° C.);

(b) general physico-chemical stability under normal storage conditions,including temperatures of between about minus 80 and about plus 50° C.(preferably between about 0 and about 40° C. and more preferably roomtemperatures, such as about 15 to about 30° C.), pressures of betweenabout 0.1 and about 2 bars (preferably at atmospheric pressure),relative humidities of between about 5 and about 95% (preferably about10 to about 75%), and/or exposure to about 460 lux of UV/visible light,for prolonged periods (i.e. greater than or equal to six months). Undersuch conditions, DDSs of the invention may be found to be less thanabout 5%, such as less than about 1% chemically degraded/decomposed, asabove;

(c) particularly importantly when the API that is employed is an opioidanalgesic, general physico-chemical stability under acidic, alkalineand/or alcoholic (e.g. ethanolic) conditions at room temperature and/orunder at elevated temperatures (e.g. up to about 100° C.), which mayresult in less than about 15% degradation, so avoiding the possibilityof deliberate ex vivo extraction of API for intended abuse (e.g. by acidor alcohol extraction, followed by injection, or heating a DDS of theinvention and then an opioid addict inhaling the vapour or smoke that isgiven off); and

(d) again, particularly importantly when the API that is employed is anopioid analgesic, general physical stability, for example with a highmechanical impact strength, so reducing the possibility of mechanicalgrinding or milling with a view to extraction of API as defined in (c)above, or by an opioid addict sniffing a resultant powder directly.

With reference to (d) above, it is preferred in this respect that DDSsof the invention exhibit a compressive strength of greater than about 10MPa, such as 50 MPa, which is high enough to withstand breakdown of thematerial at the microstructure level, i.e. of less than about 200 μm.

In this respect, we also include that DDSs of the invention maintaintheir overall integrity (e.g. shape, size, porosity, etc) when a forceof about 1 kg-force/cm2 (9 newtons/cm2), such as about 5 kg-force/cm2(45 newtons/cm2), for example about 7.5 kg-force/cm2, e.g. about 10.0kg-force/cm2, preferably about 15 kg-force/cm2, more preferably about 20kg-force/cm2, for example about 50 kg-force/cm2, especially about 100kg-force/cm2 or even about 125 kg-force/cm2 (1125 newtons/cm2) isapplied using routine mechanical strength testing techniques known tothe skilled person (for example using a so-called “compression test” or“diametral compression test”, employing a suitable instrument, such asthat produced by Instron (the “Instron Test”, in which a specimen iscompressed, deformation at various loads is recorded, compressive stressand strain are calculated and plotted as a stress-strain diagram whichis used to determine elastic limit, proportional limit, yield point,yield strength and (for some materials) compressive strength)). When thestructure of the DDS is particulate, at least about 40% (e.g. at leastabout 50%, such as at least about 60% preferably, at least about 75%,and more preferably at least about 90%) of the particles (whetherprimary or secondary particles) maintain their integrity under theseconditions.

DDSs of the invention may be incorporated into various kinds ofpharmaceutical preparations using standard techniques (see, for example,Lachman et al, “The Theory and Practice of Industrial Pharmacy”, Lea &Febiger, 3rd edition (1986) and “Remington: The Science and Practice ofPharmacy”, Gennaro (ed.), Philadelphia College of Pharmacy & Sciences,19th edition (1995)), for example to form a capsule, a powder or atablet.

The DDSs of the invention are preferably administered perorally to thegastrointestinal tract and may provide for controlled release of API inthe stomach and/or, preferably, the intestinal system.

DDS of the invention may also be presented in the form of buccal orsublingual tablets, or may even be designed for topical application.

Pharmaceutical preparations comprising DDSs of the invention contain apharmacologically effective amount of the API. By “pharmacologicallyeffective amount”, we refer to an amount of API, which is capable ofconferring a desired therapeutic effect on a treated patient, whetheradministered alone or in combination with another API. Such an effectmay be objective (i.e. measurable by some test or marker) or subjective(i.e. the subject gives an indication of, or feels, an effect).

More preferred DDSs of the invention may be adapted (for example asdescribed herein) to provide a sufficient dose of API over the dosinginterval (irrespective of the number of doses per unit time) to producea desired therapeutic effect.

The amounts of APIs that may be employed in DDSs of the invention maythus be determined by the physician, or the skilled person, in relationto what will be most suitable for an individual patient. This is likelyto vary with the route of administration, the type and severity of thecondition that is to be treated, as well as the age, weight, sex, renalfunction, hepatic function and response of the particular patient to betreated.

Suitable dosages of API in one oral delivery unit (e.g. one tablet) maybe below 1 g, preferably below 100 mg and above 1 μg.

When DDSs of the invention comprise opioid analgesics, appropriatepharmacologically effective amounts of such opioid analgesic compoundsinclude those that are capable of producing (e.g. sustained) relief ofpain when administered perorally. Thus, the total amount of opioidanalgesic API that may be employed in a DDS of the invention will dependupon the nature of the relevant API that is employed, but may be in therange of about 0.0005%, such as about 0.1% (e.g. about 1%, such as about2%) to about 20%, such as about 10%, for example about 7%, by weightbased upon the total weight of the DDS. The amount of this API may alsobe expressed as the amount in a unit dosage form. In such a case, theamount of opioid analgesic API that may be present may be sufficient toprovide a dose per unit dosage form that is in the range of betweenabout 1 μg (e.g. about 5 μg) and about 50 mg (e.g. about 15 mg, such asabout 10 mg).

The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

DDSs of the invention comprising opioid analgesics are useful in thetreatment of pain, particularly severe and/or chronic pain. According toa further aspect of the invention there is provided a method oftreatment of pain which method comprises administration of a DDS of theinvention to a person suffering from, or susceptible to, such acondition.

For the avoidance of doubt, by “treatment” we include the therapeutictreatment, as well as the symptomatic treatment, the prophylaxis, or thediagnosis, of the condition.

We have advantageously found that DDSs of the invention provide forrelease of API that is substantially uniform and/or nearly constant overan extended period of time. In one embodiment, a nearly constant rate ofrelease can vary over a dose interval from about 6 hours to about 2days. Constant release may further be defined as a DDS being capable ofmaintaining a steady state concentration in a body fluid not deviatingmore than about 20% (e.g. about 10%) from the mean value during the doseinterval. The release rate may be maintained over a long time period,corresponding approximately to the passage of time taken between initialoral administration of a DDS of the invention and excretion of thecarrier material from the body, such as between about 5 and about 24(such as about 15) hours.

DDSs of the invention possess the advantage of the avoidance and/orreduction of the risk of either dose dumping (i.e. the involuntaryrelease), or equally importantly the deliberate ex vivo extraction, ofthe majority (e.g. greater than about 50%, such as about 60%, forexample about 70% and in particular about 80%) of the dose of the API(s)that is/are initially within a DDS of the invention, either in vivo(i.e. when a DDS of the invention is administered to a patient) or exvivo (i.e. into another medium outside the body), within a timeframethat is likely to give rise to undesirable consequences, such as adversepharmacological effects (for example when such release occurs in vivo inan involuntary sense), or the potential for abuse of that API (forexample when such release is deliberately effected ex vivo by anindividual). Such dose dumping release may for example take place eitherin vivo or ex vivo within about 3 hours, such as within about 2 hours,for example within about 1 hour, and particularly within about 30minutes.

DDSs of the invention have the advantage that they provide for improvedsustained release properties with minimal risk for severe/lethal sideeffects (i.e. reduction of dose dumping and/or abuse potential when theAPI to be employed is abusable, such as an opioid, a benzodiazepine,etc.). The DDSs of the invention may provide protection againstintentional mechanical breakdown, e.g. by traditional methods such ascrushing, pestle and mortar, hammering etc by having a high compressivestrength level at the micro-level material. This protection may beprovided by the DDS of the invention as such, and especially when thoseDDSs are employed in conjunction with a carrier or filler that alsopossesses high mechanical strength.

DDSs of the invention may also have the advantage that they may beprepared using established pharmaceutical processing methods and mayemploy materials that are approved for use in foods or pharmaceuticalsor of like regulatory status.

DDSs of the invention may also have the advantage that they may be moreefficacious than, be less toxic than, be longer acting than, be morepotent than, produce fewer side effects than, be more easily absorbedthan, and/or have a better pharmacokinetic profile than, and/or haveother useful pharmacological, physical, or chemical properties over,DDSs known in the prior art, whether for use in the treatment of pain orotherwise.

Wherever the word “about” is employed herein in the context ofdimensions (e.g. values, temperatures, pressures (exerted forces),relative humidities, sizes and weights, particle or grain sizes, poresizes, timeframes etc.), amounts (e.g. relative amounts (e.g. numbers,ratios or percentages) of particles, individual constituents in aDDS/composition or a component of a DDS/composition and absoluteamounts, such as doses of APIs, numbers of particles, etc), deviations(from constants, degrees of degradation, etc) it will be appreciatedthat such variables are approximate and as such may vary by ±10%, forexample ±5% and preferably ±2% (e.g. ±1%) from the numbers specifiedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated by the following examples in which:

FIGS. 1 and 2 show the release of zolpidem (FIG. 1) and fentanyl (FIG.2) containing pellets prepared as set out in Example 1 (Table 1) in pH6.8.

FIG. 3 shows average compression strength of zolpidem containing DDSs(rods) prepared as set out in Example 1. The error bars represent themaximum and minimum compression strength measured for at least 5compression rods.

EXAMPLES Example 1

Different geopolymers (see Table 1 below) were prepared by mixingrelevant API (fentanyl base (Johnson Matthey MacFarlan & Smith (UK)) orzolpidem tartrate (Cambrex Charles City Inc (USA)); <1 wt %), metakaolin(prepared by heating kaolin (Sigma-Aldrich, Sweden AB) at 800° C. for 2hours) and different waterglasses (sodium silicate solutions; preparedby mixing different amounts of deionized water with aqueous solutionscontaining dissolved SiO2 and NaOH) into a homogeneous paste in a glassmortar.

The paste was subsequently transferred to a pellet Teflon®-mould withcylindrically shaped holes with a size of 1.5×1.5 mm (diameter×height).The mould was in turn placed in an oven set to 40° C. for 48 hours tocomplete geopolymerisation.

TABLE 1 Molar ratios of the different compounds of the samples togetherwith the sample porosities and the API release process diffusioncoefficients (Abbrev. Zol = zolpidem sample; Fen = fentanyl sample)Molar Ratio D (pH 6.8)¹ Porosity ε² Sample H₂O/SiO₂ Na₂O/SiO₂ Si/Al[10⁻⁹ cm²/s] [%] Zol1 2.6 0.28 1.76 —  22 ± 13 Zol2 3.4 0.28 1.76 — 21 ±7 Zol3 4.5 0.49 1.76 — 19 ± 6 Zol4 5.9 0.50 1.76 45.5 ± 2.3 32 ± 6 Zol53.5 0.33 1.55 — 28 ± 3 Zol6 5.5 0.44 1.55 24.3 ± 2.1 49 ± 6 Zol7 4.30.33 1.32  7.8 ± 0.1 36 ± 6 Zol8 4.5 0.42 1.32  9.6 ± 1.3  44 ± 16 Zol94.3 0.28 1.06 11.1 ± 1.3 44 ± 4 Zol10 4.3 0.33 1.06 10.1 ± 2.1 49 ± 6Zol11 4.5 0.49 1.06 13.3 ± 2.6 41 ± 6 Zol12 5.9 0.49 1.06 19.4 ± 4.1 50± 7 Fen3 4.5 0.49 1.77 — — Fen5 3.6 0.33 1.55 — — Fen8 4.6 0.42 1.32 6.1— Fen9 4.3 0.28 1.06 6.3 — Fen10 4.4 0.33 1.06 2.7 — Fen11 4.5 0.50 1.062.2 —1 The displayed error values represent absolute deviation of diffusioncoefficients for 2-3 measurements on Zol pellet samples from differentbatches. The diffusion coefficients of Fen samples were mainly extractedfrom measurements performed on pellets from a single batch, butmeasurements on reformulated DDSs displayed errors less than 7%.2 Since the samples contain less than 1% API, the porosities were onlymeasured for the zolpidem-containing samples. The error values representabsolute deviations for 10 consecutive measurements cycles.

The release of API from the relevant pellets was carried out in a USP-2dissolution bath (Sotax AT 7, Sotax AG, Switzerland) equipped with 200mL vessels (37° C., 50 rpm). 150 μg of pellets were placed in eachvessel and 1 mL liquid was withdrawn from each vessel 8 to 9 timesduring the time of release. Release measurements were performed in aphosphate buffer at pH 6.8 and in 0.1M HCl (pH 1.0). The concentrationof API in the liquid samples was analyzed with a high performance liquidchromatography system (HPLC, Dionex Summit HPLC system, Dionex corp.,Sunnyvale, Calif.). 1M HCl was added to the pH 6.8 liquid samplescontaining fentanyl to stabilize the API in the media prior to HPLCanalysis (0.9 mL sample/0.1 mL IM HCl). The withdrawn pH 1.0 samplescontaining zolpidem were diluted with IM NaOH to enable correctchromatography analysis (0.8 mL sample/0.2 mL 1M NaOH).

The compressive strengths of the different DDSs were tested with anAutograph AGS-H universal testing machine (Shimadzu corp., Japan). Eightto ten cylindrical rods of each DDS with the dimensions 6×12 mm(diameter×height) were tested and the averages calculated.

In relation to diffusion coefficients (D), when the initial API contentin a rigid delivery vehicle was below the solubility limit of the APIand the API dissolution was fast enough to not be a releaserate-limiting factor, the API release was assumed to be governed bymolecular diffusion through the network of pores of the deliveryvehicle. On the assumption that isotropic API release and uniform APIloading, whereby the API instantaneously dissolves as the dissolutionliquid enters the pore system, the total released API fraction Q as afunction of time may be expressed as:

Here D is the diffusion coefficient of the API molecules, where is thei:th zero of the Bessel function J0-(r), ßj=(2j−1) □/2H, where R and Hare the radius and height of the cylindrical pellets, respectively.

The porosities of the DDSs were assessed by measurement of the apparentand true densities. The apparent density—i.e. the sample mass divided bythe total volume of solid, Vtot, including all pores, Vpores—wasobtained by averaging the ratio of mass to volume measured with a slidecaliper for the pellets. The true density—i.e. the sample mass dividedby the skeletal volume of solid—was measured using He pycnometry(AccuPyc 1340, Micromeritics Corp., USA). Helium is assumed to penetrateall pores wider than 0.1-0.2 nm. In effect, the true density, of a solidwill always be larger than or equal to its apparent density. Theporosity, ε, was hence calculated as:

The zeta potential of crushed and mortared geopolymer was measured witha Zetasizer (Malvern, UK). The potential was measured in aqueoussolutions of pH 6.8 and pH 1.0 at 25° C.

The release of zolpidem (Zol1-12) and fentanyl (Fen3-11) in phosphatebuffer (pH 6.8) is shown in FIGS. 1 and 2, respectively. The totalamount of API released after 24 hours was approximately the same for allDDSs, namely between about 80 and 95%, with the values for fentanylbeing somewhat higher than those for zolpidem, excepting the DDSs thatcontained higher amounts of silica and simultaneously low amounts ofwater (high Si/Al ratio and low H2O/SiO2 ratio, see Table 1 above); viz.Zol1-3, and Zol5 as well as Fen3 and Fen5.

It was found that increasing the amount of water tended to open up thestructure and extend the setting time, apparently allowing more time andspace for reorganization, i.e. dissolution of the precursor material andre-precipitation of the inorganic polymer structure. This was mostmarkedly seen when comparing the release profiles for Zol3 and Zol4 inFIG. 1. The higher water content of Zol4, cf. Table 1, clearly resultedin a larger amount of released API. The same observation was made whencomparing Zol5 and Zol6, and also very slightly for Zol7 and Zol8; anincreased amount of water in the structure led to a higher amount of APIbeing released.

It was apparent that an increase in H2O/SiO2 ratio with a simultaneousdecrease in Si/Al ratio shifted the pore distribution maximum from the5-10 nm range for the Zol1-3 samples to 40-50 nm for the Zol6-7 samplesand even out of the measurement range (300 nm) for the applied analysismethod for the Zol11-Zol12 samples.

Furthermore, decreasing the Si content as well as increasing the watercontent clearly increased the porosity, which was assessed by comparingthe apparent and skeletal density of the samples (see Table 1). Theincrease in measured porosity is most likely due to both a larger porevolume and a more interconnected pore structure in the pellets, whichallowed the analysis gas to penetrate the structures more effectively.

FIG. 3 displays the compression strength of twelve different Zolpidemcontaining samples with compression strengths ranging from 10 to ˜100MPa. It is observed that geopolymer structures with low porosity (highSi/Al ratios, low H2O/SiO2 ratios) are reported to have the higheststrengths. Both size and geometry of the pores as well as the relativepore volume in the structure appears to affect the strength of ceramicmaterials such as geopolymers. By minimizing the relative pore volume inthe structure, the applied load can spread over a larger area and theinternal stress can be minimized and, thus, increase the compressionstrength of the material.

From FIG. 3, it can also be observed that a higher alkali content(Na2O/SiO2 ratio) rendered a stronger geopolymer structure (e.g. Zol8stronger than Zol7, Zol11 stronger than Zol10 stronger than Zol9).Unreacted particles may increase the strength of the structure. Thehigher alkali content may also promote reorganization and densificationof the binder phase which in turn also increases the compressionstrength.

Even though the Zol3 compression rods cracked, the corresponding pelletsstayed intact during handling and during the API release measurements.They displayed a more linear release behaviour (FIGS. 1 and 2) of bothZolpidem and Fentanyl (Zol3; Fen3) than did the other DDSs.

The diffusion coefficients, D, of the APIs in the studied geopolymerpellets were extracted to quantify the speed of the API release process(Table 1). The coefficients were obtained by fitting a mathematicalsolution to the diffusion equation (Fick's second law; see Crank, TheMathematics of Diffusion (Clarendon Press, Oxford, 1975)) for a uniformcylindrical body with zero concentration (perfect sink) boundaryconditions on all surfaces. In general, the fitting was found to be ofvery good quality.

The diffusion coefficients proved to be affected by the amount of waterused at the preparation of the pellets. A larger amount of water appearsto render higher diffusion coefficients and, thus, a more rapid release.The Zolpidem containing DDSs containing the highest amount of water(Zol4, Zol6, and Zol12) released more than 50% of their API within 6hours.

The release of Fentanyl was somewhat slower than the Zolpidem release(Table 1), although the release rates of the APIs from the differentDDSs are almost equal to each other at pH 1.0. There is nevertheless asustained release of API for at least 4 hours at pH 1.0.

The invention claimed is:
 1. A sustained release pharmaceuticalcomposition comprising an active pharmaceutical ingredient, or apharmaceutically acceptable salt thereof, and a geopolymeric binder,wherein the composition maintains a steady state concentration in a bodyfluid not deviating more than about 20% from the mean value over a doseinterval from about 6 hours to about 2 days.
 2. The composition asclaimed in claim 1, characterised in that the active pharmaceuticalingredient is combined with the geopolymeric binder during the formationof that binder.
 3. The composition as claimed in claim 1, wherein theactive pharmaceutical ingredient is an opioid analgesic.
 4. Thecomposition as claimed in claim 3, wherein the opioid analgesic isselected from buprenorphine, alfentanil, sufentanil, remifentanil andfentanyl.
 5. The composition as claimed in claim 4, wherein the opioidanalgesic is fentanyl.
 6. A composition as claimed in claim 1, whereinthe active pharmaceutical ingredient, or pharmaceutically acceptablesalt thereof, is uniformly loaded throughout the geopolymeric binder. 7.A composition as claimed in claim 1, wherein the geopolymeric binder isobtainable by reaction of an aluminosilicate precursor material with anaqueous alkaline liquid.
 8. A composition as claimed in claim 7, whereinthe aluminosilicate phase is selected from the group consisting ofkaolin, dickite, halloysite, nacrite, zeolite, illite, dehydroxylatedzeolite, dehydroxylated halloysite and dehydroxylated kaolin.
 9. Acomposition as claimed in claim 7, wherein the reaction of takes placein the presence of a source of silica.
 10. A composition as claimed inclaim 1, wherein the geopolymeric binder has the general compositionM₂O*xSiO₂ *yAl₂O₃ *zH₂O wherein M is an alkali metal cation; x is in therange of 0.1-300; y is in the range of 0.1-100; and z is in the range of0.1-100.
 11. A composition as claimed in claim 1, wherein thecomposition comprises a film-forming agent.
 12. A method of treatment ofpain which comprises administration of a composition as defined in claim3 to a person suffering from, or susceptible to, such a condition.
 13. Amethod of treatment of pain which comprises administration of acomposition as defined in claim 4 to a person suffering from, orsusceptible to, such a condition.
 14. A method of treatment of painwhich comprises administration of a composition as defined in claim 5 toa person suffering from, or susceptible to, such a condition.